Summary Infections caused by Staphylococcus aureus are more frequent and severe in people with both type 1 diabetes (T1D) and T2D than in healthy individuals. For over a century, it has been suggested that phagocytes from people with diabetes show poor antimicrobial functions, which created the paradigm that diabetes leads to immunosuppression. However, hyperglycemia also drives an excessive production of inflammatory mediators by immune cells. Here, we will take our current knowledge in host defense and diabetes in a different direction. We speculated that increased susceptibility to infection is due to an uncontrolled localized inflammatory response that causes skin damage and prevents bacterial elimination. We recently showed that S. aureus skin infection in diabetic mice was accompanied by unrestrained neutrophil migration to the site of infection, increased the production of inflammatory mediators, poor abscess formation (a structure that prevents spread to deeper tissues and systemic infection) and impaired bacterial clearance. We also showed inadequate production of the pleiotropic lipid mediator prostaglandin E2 (PGE2) in the skin of infected diabetic mice and a topical ointment containing misoprostol (an FDA-approved PGE analog) restored bacterial clearance during diabetes. Our preliminary data reveal low PGE2 production could be due to a reduced capacity to phagocytes to ingest and clear dead cells (efferocytosis), leading to secondary necrosis, leakage of endogenous inflammatory mediators, tissue injury and poor host defense. We are hypothesizing that deficient efferocytosis during MRSA skin infection in diabetic mice is responsible for low PGE2 production, which increases inflammation-associated tissue damage and prevents wound healing to ultimately enhance susceptibility to non-healing skin infections. We will utilize transgenic mice producing constitutively PGE2 and fluorescent phagocytes, along with state-of-the-art techniques, including imaging mass spectrometry (IMS), in vivo imaging (IVIS) and intravital microscopy imaging (IVM) to unveil the role of PGE2 levels, the E prostanoid receptors and downstream effectors in tissue repair during skin infection in people and mice with diabetes (Aim 1). Next, we are postulating that misoprostol improves wound healing in the infected skin by increasing the production of actions of the second messenger cyclic adenosine monophosphate (cAMP) downstream effectors involved in misoprostol-improved host defense in diabetic mice (Aim 2). In the Aim 3, we will study whether the failure of a repair mechanism involved in the elimination of dead cells (efferocytosis) leads to deficient PGE2 production and generation of inflammatory mediators, causing tissue injury in the infected skin of diabetic mice. Our project could rapidly translate into clinical use to improve the treatment of skin infection in patients with diabetes. With antimicrobial resistance and increasing prevalence of diabetes worldwide, there is a compelling need for safe, inexpensive, non-antibiotic, and host-centered approaches to prevent and treat infections.